Method and treatment using 1-methylcarbapenem derivatives as an anti-helicobacter pylori agent

Abstract

A method for the prophylaxis or treatment of infectious diseases caused by helicobacter pyloir, by administering a pharmacologically effective amount of a 1-methoylcarbapenem coumpund of formula (I) or a pharmacologically acceptable salt or ester thereof: ##STR1##

R¹ represents a group of the following formula: ##STR2##

R² is a hydrogen atom or a c₁ -c₆ alkyl group, and R³ is a hydrogen atom or a c₁ -c₆ alkyl group.

Description

This application is a continuation application of International Application PCT/JP97/01542 filed May 8, 1997.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to an anti-helicobacter pylori composition comprising 1-methylcarbapenem derivatives or pharmacologically acceptable salts or esters thereof as an active ingredient, use of the derivatives, salts or esters for the preparation of an anti-helicobacter pylori medicament and a method which comprises administering a pharmacologically effective amount of the derivatives, salts or esters to warm-blooded animals for treatment and prevention of infectious diseases caused by helicobacter pylori.

2. Background Information

According to recent studies, there are a number of reports on the phenomenon that helicobacter pylori is detected at a high ratio in patients suffering from chronic gastritis or digestive ulcers, and that such gastrointestinal disorders are cured by the eradication of helicobacter pylori; and on the phenomenon that the recurrence ratio of digestive ulcers shows a drastic decrease as a result of the eradication of this bacterium. It is therefore thought that infection with this bacterium relates to chronic and digestive ulcers and, furthermore, it even has a close relationship with gastric cancer or gastritis (G. E. Buck et al., J. Infect. Dis., 153, 664-669(1986), G. Geis et al., J. Clinical Microbiology, 930-932(1990), etc.).

At present, it is reported that bismuth compounds such as bismuth citrate, nitroimidazole compounds such as metronidazole and antibiotics such as tetracycline, amoxicillin and clarithromycin are effective against helicobacter pylori. None of these compounds has sufficient antibacterial activity and each has a chemical structure markedly different from that of the 1-methylcarbapenem derivatives which are an active ingredient to be employed in the present invention.

The 1-methylcarbapenem derivatives, which are an active ingredient of the present invention, are known compounds (for example, Japanese Patent Publication No. Hei 745499, Japanese Patent Application Kokai No. Hei 2-223587, Japanese Patent Application Kokai No. Hei 4-279588, Japanese Patent Application Kokai No. Hei 8-53453 etc.), but their anti-helicobacter pylori activity is not known at all.

SUMMARY OF THE INVENTION

The present inventors have carried out an extensive investigation into the antibacterial activity of 1-methylcarbapenem derivatives. As a result, it has been found that specific 1-methylcarbapenem derivatives have excellent anti-helicobacter pylori activity and are useful as an active ingredient in an anti-helicobacter pylori composition (treatment or prevention of infectious diseases caused by helicobacter pylori, particularly, treatment).

The present invention provides an anti-helicobacter pylori composition comprising 1-methylcarbapenem derivatives or pharmacologically acceptable salts or esters thereof as an active ingredient, use of the derivatives, salts or esters for the preparation of an anti-helicobacter pylori medicament and a method comprising administering a pharmacologically effective amount of the derivatives, salts or esters to warm-blooded animals for treatment and prevention of infectious diseases caused by helicobacter pylori.

1-Methylcarbapenem derivatives, an active ingredient of the present invention, have the following formula: ##STR3##

wherein R¹ represents a group of the following formula: ##STR4##

R² represents a hydrogen atom or a C₁ -C₆ alkyl group, and

R³ represents a hydrogen atom or a C₁ -C₆ alkyl group.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting the effect of the treatment on mice.

DETAILED DESCRIPTION OF THE INVENTION

In the above formula (I), examples of the C₁ -C₆ alkyl group of R² or R³ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl t-butyl, pentyl and hexyl groups, preferably the C₁ -C₄ alkyl groups, more preferably the methyl or ethyl group and most preferably the methyl group.

R¹ is preferably the group of the formula (Ila).

The oxopyrrolidinyl part of the group of the formula (la) is preferably a 2-oxo-3-pyrrolidinyl or 2-oxo-4-pyrolidinyl group and most preferably the 2-oxo4-pyrrolidinyl group.

The thioxopyrrolidinyl part of the group of the formula (IId) is preferably a 2-thioxo-3-pyrrolidinyl or 2-thioxo-4-pyrrolidinyl group, and most preferably the 2-thioxo4-pyrrolidinyl group.

The pharmacologically acceptable salts of Compound (I) which are also an active ingredient of the present invention are salts of Compound (I) which exhibit antibacterial activity and are usable as a medicament when administered to a living body. Examples include inorganic salts such as lithium salts, sodium salts, potassium salts, calcium salts and magnesium salts; ammonium salts; and organic amine salts such as triethylamine salts, diisopropylamine salts and cyclohexylamine salts; preferably lithium salts, sodium salts and potassium salts; more preferably sodium salts and potassium salts; and most preferably sodium salts.

The pharmacologically acceptable esters of Compound (I) which are also an active ingredient of the present invention are esters of the compound (I) which exhibit antibacterial activity and are usable as a medicament when administered to a living body; and preferably esters which can be hydrolyzed in vivo and converted to the corresponding carboxylic acids. Specific examples include:

C₁ -C₄ alkyl esters (preferably, methyl and ethyl esters),

C₁ -C₄ alkoxycarbonyloxy-(C₁ -C₄ alkyl) esters [for example, methoxycarbonyloxymethyl esters, 1-(methoxycarbonyloxy)ethyl esters, ethoxycarbonyloxymethyl esters, 1-(ethoxycarbonyloxy)ethyl esters, propoxycarbonyloxymethyl esters, 1-(propoxycarbonyloxy)ethyl esters, isopropoxycarbonyloxymethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, butoxycarbonyloxymethyl esters, 1-(butoxycarbonyloxy)ethyl esters, isobutoxycarbonyloxymethyl esters, 1-(isobutoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters, 1-(t-butoxycarbonyloxy)ethyl esters, 1-(t-butoxycarboyloxy)propyl esters and 1-(t-butoxycarbonyloxy)butyl esters, of which the methoxycarbonyloxymethyl esters, 1-(methoxycarbonyloxy)ethyl esters, ethoxycarbonyloxymethyl esters, 1-(ethoxycarbonyloxy) ethyl esters, isopropoxycarbonyloxymethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters or 1-(t-butoxycarbonyloxy)ethyl esters are preferred, the 1-(methoxycarbonyloxy)ethyl esters, 1-(ethoxycarbonyloxy)ethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters and 1-(t-butoxycarbonyloxy)ethyl esters being more preferred and the 1-(isopropoxycarbonyloxy)ethyl esters being most preferred],

C₅ -C₆ cycloalkyloxycarbonyloxy-(C₁ -C₄ alkyl) esters [for example, cyclopentyloxycarbonyloxymethyl esters, 1-(cyclopentyloxycarbonyloxy)ethyl esters, cyclohexyloxycarbonyloxymethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)propyl esters and 1-(cyclohexyloxycarbonyloxy)butyl esters, of which the cyclopentyloxycarbonyloxymethyl esters, 1-(cyclopentyloxycarbonyloxy)ethyl esters, cyclohexyloxycarbonyloxymethyl esters and 1-(cyclohexyloxycarbonyloxy)ethyl esters are preferred, the 1-(cyclopentyloxycarbonyloxy)ethyl esters and 1-(cyclohexyloxycarbonyloxy)ethyl esters being more preferred, and the 1-(cyclohexyloxycarbonyloxy)ethyl esters being most preferred;

C₂ -C₅ alkanoyloxy-(C₁ -C₄ alkyl) esters [for example, acetoxymethyl esters, 1-(acetoxy)ethyl esters, 1-(acetoxy)propyl esters, 1-(acetoxy)butyl esters, propionyloxymethyl esters, 1-(propionyloxy)ethyl esters, butyryloxymethyl esters, 1-(butyryloxy)ethyl esters, isobutyryloxymethyl esters, 1-(isobutyryloxy)ethyl esters, 1-(isobutyryloxy)propyl esters, 1-(isobutyryloxy)butyl esters, pivaloyloxymethyl esters, 1-(pivaloyloxy)ethyl esters, 1-(pivaloyloxy)propyl ester and 1-(pivaloyloxy)butyl esters, of which the acetoxymethyl esters, 1-(acetoxy)ethyl esters, propionyloxymethyl esters, 1-(propionyloxy)ethyl esters, butyryloxymethyl esters, 1-(butyryloxy)ethyl esters, isobutyryloxymethyl esters, 1-(isobutyryloxy)ethyl esters, pivaloyloxymethyl esters and 1-(pivaloyloxy)ethyl esters are preferred, the acetoxymethyl esters, 1-(acetoxy)ethyl esters, isobutyryloxymethyl esters, 1-(isobutyryloxy)ethyl esters, pivaloyloxymethyl esters and 1-(pivaloyloxy)ethyl esters being more preferred, and the pivaloyloxymethyl esters being most preferred];

(C₅ -C₆ cycloalkylcarbonyloxy)- or (1-alkyl-C₅ -C₆ cycloalkylcarbonyloxy)-(C₁ -C₄ alkyl) esters [for example, cyclopentylcarbonyloxymethyl esters, 1-(cyclopentylcarbonyloxy)ethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, 1-(1-methylcyclopentylcarbonylxoy)ethyl esters, 1-ethylcyclopentylcarbonyl-oxymethyl esters, 1(1-ethylcyclopentylcarbonyloxy)ethyl esters, cyclohexylcarbonyloxymethyl esters, 1-(cyclohexylcarbonyloxy)ethyl esters, 1-(cyclohexylcarbonyloxy)propyl esters, 1-(cyclohexylcarbonyloxy)butyl esters, 1-methylcyclohexylcarbonyloxymethyl esters, 1-(1-methylcyclohexylcarbonyloxy)ethyl esters, 1-(1-methylcyclohexylcarbonyloxy)propyl esters, 1-(1-methylcyclohexylcarboyloxy)butyl esters, 1-ethylcyclohexylcarbonyloxymethyl esters, 1-(1-ethylcyclohexylcarbonyloxy)ethyl esters, 1(1-propylcyclohexylcarbonyloxymethyl esters and 1-butylcyclohexylcarbonyloxymethyl esters, of which the cyclopentylcarbonyloxymethyl esters, 1-(cyclopentylcarbonyloxy)ethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, 1-(1-methylcyclopentylcarbonyloxy)ethyl esters, 1-ethylcyclopentylcarbonyloxymethyl esters, cyclohexylcarbonyloxymethyl esters, 1-(cyclohexylcarbonyloxy)ethyl esters, 1-methylcyclohexylcarbonyloxymethyl esters, 1-(1-methylcyclohexylcarbonyloxy)ethyl esters and 1-ethylcyclohexylcarbonyloxymethyl esters are preferred, the cyclopentylcarbonyloxymethyl esters, 1-(cyclopentylcarbonyloxy)ethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, 1(1-methylcyclopentylcarbonyloxy)ethyl esters, cyclohexylcarbonyloxymethyl esters, 1-(cyclohexylcarbonyloxy)ethyl esters, 1-methylcyclohexylcarbonyloxymethyl esters and 1-(1 -methylcyclohexylcarbonyloxy)ethyl esters being more preferred, the cyclopentylcarbonyloxymethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, cyclohexylcarbonyloxymethyl esters and 1-methylcyclohexylcarbonyloxymethyl esters being much more preferred, and the 1-methylcyclohexylcarbonyloxymethyl esters being most preferred];

phthalidyl esters; and

5-(C₁ -C₄ alkyl- or phenyl-)-2-oxo-1,3-dioxolen 4ylmethyl esters [for example, 5-methyl-2-oxo-1,3-dioxoleno-4-ylmethyl esters, 5-ethyl-2-oxo-1,3-dioxolen-4-ylmethyl esters, 5-propyl-2-oxo-1,3-dioxolen-4-ylmethyl esters, 5-butyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl esters, of which the 5-methyl-2-oxo-1,3-dioxolen4-ylmethyl esters, 5-ethyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and 5-phenyl-2-oxo-1,3-dioxolen4-ylmethyl esters are preferred, the 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl esters being more preferred, and the 5-methyl-2-oxo-1,3-dioxolen4-ylmethyl esters being most preferred].

Among these esters, the methoxycarbonyloxymethyl esters, 1-(methoxycarbonyloxy)ethyl esters, ethoxycarbonyloxymethyl esters, 1-(ethoxycarbonyloxy)ethyl esters, isopropoxycarbonyloxymethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters, 1-butoxycarbonyloxy)ethyl esters, cyclopentyloxycarbonyloxymethyl esters, 1-(cyclopentyloxycarbonyloxy)ethyl esters, cyclohexyloxycarbonyloxymethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters, acetoxymethyl esters, 1-(acetoxy)ethyl esters, propionyloxymethyl esters, 1-(propionyloxy)ethyl esters, butyryloxymethyl esters, 1-(butyryloxy)ethyl esters, isobutyryloxymethyl esters, 1-(isobutyryloxy)ethyl esters, pivaloyloxymethyl esters, 1-(pivaloyloxy)ethyl esters, cyclopentylcarbonyloxymethyl esters, 1-(cyclopentylcarbonyloxy)ethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, 1-(1-methylcyclopentylcarbonyloxy)ethyl esters, 1-ethylcyclopentylcarbonyloxymethyl esters, cyclohexylcarbonyloxymethyl esters, 1-(cyclohexylcarbonyloxy)ethyl esters, 1-methylcyclohexylcarbonyloxymethyl esters, 1-(1-methylcyclohexylcarbonyloxy)ethyl esters, 1-ethylcyclohexylcarbonyloxymethyl esters, phthalidyl esters, 5-methyl-2-oxo-1,3-dioxolen4-ylmethyl esters, 5-ethyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl esters are preferred;

the 1-(methoxycarbonyloxy)ethyl esters, 1-(ethoxycarbonyloxy)ethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters, 1-(t-butoxycarbonyloxy)ethyl esters, 1-(cyclopentyloxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters, acetoxymethyl esters, 1-(acetoxy)ethyl esters, isobutyryloxymethyl esters, 1-isobutyryloxy)ethyl esters, pivaloyloxymethyl esters, 1-(pivaloyloxy)ethyl esters, cyclopentylcarbonyloxymethyl esters, 1-(cyclopentylcarbonyloxy)ethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, 1-(1-methylcyclopentylcarbonyloxy)ethyl esters, cyclohexylcarbonyloxymethyl esters, 1-(cyclohexylcarbonyloxy)ethyl esters, 1-methylcyclohexylcarbonyloxymethyl esters, 1-(1-methylcyclohexylcarbonyloxy)ethyl esters, phthalidyl esters, 5-methyl-2-oxo-1,3-dioxolen4-ylmethyl esters and 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl esters are more preferred;

the 1-(methoxycarbonyloxy)ethyl esters, 1-(ethoxycarbonyloxy)ethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters, 1-(t-butoxycarbonyloxy)ethyl esters, 1-(cyclopentyloxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters, acetoxymethyl esters, 1-(acetoxy)ethyl esters, isobutyryloxymethyl esters, 1-(isobutyryloxy)ethyl esters, pivaloyloxymethyl esters, 1-(pivaloyloxy)ethyl esters, cyclopentylcarbonyloxymethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, cyclohexylcarbonyloxymethyl esters, 1-methylcyclohexylcarbonyloxymethyl esters, phthalidyl esters and 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters are still more preferred;

the 1-(isopropoxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters, pivaloyloxymethyl esters, 1-methylcyclohexylcarboyloxymethyl esters and 5-methyl-2-oxo-1,3-dioxolen 4ylmethyl esters are particularly preferred; and

the 1-(isopropoxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters and pivaloyloxymethyl esters are most preferred.

Compound (I) which is an active ingredient of the present invention contains asymmetric carbons in its molecule and therefore has various isomers with respect to them. The present application embraces various isomers of Compound (I) and mixtures of these isomers, of which the isomers having a (1R,5S,6S) configuration and an R configuration for the hydroxyl group at the α-position of the 6-substituent in the carbapenem skeleton, are preferred. The present application also embraces hydrated products of Compound (I) and its salts and esters.

Preferred examples of the compounds of formula (I) include:

(1) a compound wherein R¹ represents a group of formula (IIa) (in which R² represents a hydrogen atom or a C₁ -C₄ alkyl group), a group of formula (IIb), a group of formula (IIc) or a group of formula (IId) (in which R³ represents a hydrogen atom or a methyl group),

(2) a compound wherein R¹ represents a group of formula (IIa) (in which R² represents a hydrogen atom or a methyl group),

(3) a compound wherein R¹ represents a 2-oxo-3-pyrrolidinyl, 1-methyl-2-oxo-3-pyrrolidinyl, 2-oxo-4-pyrrolidinyl or 1-methyl-2-oxo4-pyrrolidinyl group,

(4) a compound wherein R¹ represents a 2-oxo4-pyrrolidinyl or 1 -methyl-2-oxo-4-pyrrolidinyl group,

(5) a compound wherein R¹ represents a 2-oxo-4pyrrolidinyl group,

(6) a compound wherein the configuration in the carbapenem skeleton is a (1R,5S,6S) configuration,

(7) a compound wherein the configuration of the hydroxyl group at the α-position of the 6-substituent in the carbapenem skeleton is a R configuration,

(8) a compound whose pharmacologically acceptable salt is a lithium salt, sodium salt or potassium salt,

(9) a compound whose pharmacologically acceptable salt is a sodium salt or potassium salt,

(10) a compound whose pharmacologically acceptable salt is a sodium salt,

(11) a compound whose pharmacologically acceptable ester can be hydrolyzed in vivo and converted into the corresponding carboxylic acid,

(12) a compound whose pharmacologically acceptable ester is a 1-(methoxycarbonyloxy)ethyl ester, 1-(ethoxycarbonyloxy)ethyl ester, 1-(isopropoxycarbonyloxy)ethyl ester, t-butoxycarbonyloxymethyl ester, 1-(t-butoxycarbonyloxy)ethyl ester, 1-(cyclopentyloxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, acetoxymethyl ester, 1-(acetoxy)ethyl ester, isobutyryloxymethyl ester, 1-(isobutyryloxy)ethyl ester, pivaloyloxymethyl ester, 1-(pivaloyloxy)ethyl ester, cyclopentylcarbonyloxymethyl ester, 1-(cyclopentylcarbonyloxy)ethyl ester, 1-methylcyclopentylcarbonyloxymethyl ester, 1-(1-methylcyclopentylcarbonyloxy)ethyl ester, cyclohexylcarbonyloxymethyl ester, 1-(cyclohexylcarbonyloxy)ethyl ester, 1-methylcyclohexylcarbonyloxymethyl ester, 1-(1-methylcyclohexylcarbonyloxy)ethyl ester, phthalidyl ester, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester or 5-phenyl-2-oxo-1,3-dioxolen4-ylmethyl ester,

(13) a compound whose pharmacologically acceptable ester is a 1-(methoxycarbonyloxy)ethyl ester, 1-(ethoxycarbonyloxy)ethyl ester, 1-(isopropoxycarbonyloxy)ethyl ester, t-butoxycarbonyloxymethyl ester, 1-(t-butoxycarbonyloxy)ethyl ester, 1-(cyclopentyloxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, acetoxymethyl ester, 1-(acetoxy)ethyl ester, isobutyryloxymethyl ester, 1-(isobutyryloxy)ethyl ester, pivaloyloxymethyl ester, 1-(pivaloyloxy)ethyl ester, cyclopentylcarbonyloxymethyl ester, 1-methylcyclopentylcarbonyloxymethyl ester, cyclohexylcarbonyloxymethyl ester, 1-methylcyclohexylcarboyloxymethyl ester, phthalidyl ester or 5-methyl-2-oxo-1,3-dioxolen4-ylmethyl ester,

(14) a compound whose pharmacologically acceptable ester is a 1-(isopropoxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, pivaloyloxymethyl ester, 1-methylcyclohexylcarbonyloxymethyl ester or 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, and

(15) a compound whose pharmacologically acceptable ester is a 1-(isopropoxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester or pivaloyloxymethyl ester.

In each of the groups (1) to (5), (8) to (10) and (11) to (15), the larger the number is, the more preferred the compound is.

In addition, compounds obtained by selecting R¹ from the group (1) to (5), a configuration from (6) or (7), a salt from the group (8) to (10) and an ester from the group (11) to (15) and by using these in any combination are preferred. Examples of such compounds are as follows:

(16) a compound wherein R¹ represents a group of formula (Ila) (in which R² represents a hydrogen atom or a C₁ -C₄ alkyl group), group of formula (IIb), group of formula (IIc) or group of formula (IId) (in which R³ represents a hydrogen atom or a methyl group),

the configuration in the carbapenem skeleton is a (1R,5S,6S) configuration,

the configuration of the hydroxyl group at the α-position of the 6-substituent in the carbapenem skeleton is a R configuration,

the pharmacologically acceptable salt is a lithium salt, sodium salt or potassium salt, and

the pharmacologically acceptable ester is one which can be hydrolyzed in vivo and converted into the corresponding carboxylic acid.

(17) a compound wherein R¹ represents a group of formula (IIa) (in which R² represents a hydrogen atom or a methyl group),

the configuration in the carbapenem skeleton is a (1R,5S,6S) configuration,

the configuration of the hydroxyl group at the α-position of the 6-substituent in the carbapenem skeleton is a R configuration,

the pharmacologically acceptable salt is a sodium salt or potassium salt, and

the pharmacologically acceptable ester is a 1-(methoxycarbonyloxy)ethyl ester, 1-(ethoxycarbonyloxy)ethyl ester, 1-(isopropoxycarbonyloxy)ethyl ester, t-butoxycarbonyloxymethyl ester, 1-(t-butoxycarbonyloxy)ethyl ester, 1-(cyclopentyloxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, acetoxymethyl ester, 1-(acetoxy)ethyl ester, isobutyryloxymethyl ester, 1-(isobutyryloxy)ethyl ester, pivaloyloxymethyl ester, 1-(pivaloyloxy)ethyl ester, cyclopentylcarbonyloxymethyl ester, 1-(cyclopentylcarbonyloxy)ethyl ester, 1-methylcyclopentylcarbonyloxymethyl ester, 1-(1-methylcyclopentylcarbonyloxy)ethyl ester, cyclohexylcarbonyloxymethyl ester, 1-(cyclohexylcarbonyloxy)ethyl ester, 1-methylcyclohexylcarbonyloxymethyl ester, 1-(1-methylcyclohexylcarbonyloxy)ethyl ester, phthalidyl ester, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester or 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl ester,

(18) a compound wherein R¹ represents a 2-oxo-3-pyrrolidinyl group, 1-methyl-2-oxo-3-pyrrolidinyl group, 2-oxo-4-pyrrolidinyl group or 1-methyl-2-oxo-4-pyrrolidinyl group,

the configuration in the carbapenem skeleton is a (1R,5S,6S) configuration,

the configuration of the hydroxyl group at the α-position of the 6-substituent in the carbapenem skeleton is a R configuration,

the pharmacologically acceptable salt is a sodium salt or potassium salt, and

the pharmacologically acceptable ester is a 1-(methoxycarbonyloxy)ethyl ester, 1-(ethoxycarbonyloxy)ethyl ester, 1-(isopropoxycarbonyloxy)ethyl ester, t-butoxycarbonyloxymethyl ester, 1-(t-butoxycarbonyloxy)ethyl ester, 1-(cyclopentyloxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, acetoxymethyl ester, 1-acetoxy)ethyl ester, isobutyryloxymethyl ester, 1-(isobutyryloxy)ethyl ester, pivaloyloxymethyl ester, 1-(pivaloyloxy)ethyl ester, cyclopentylcarbonyloxymethyl ester, 1-methylcyclopentylcarbonyloxymethyl ester, cyclohexylcarbonyloxymethyl ester, 1-methylcyclohexylcarboyloxymethyl ester, phthalidyl ester or 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester,

(19) compounds wherein R¹ represents a 2-oxo-4-pyrrolidinyl group or 1-methyl-2-oxo-4-pyrrolidinyl group,

the configuration in the carbapenem skeleton is a (1R,5S,6S) configuration,

the configuration of the hydroxyl group at the a-position of the 6-substituent in the carbapenem skeleton is a R configuration,

the pharmacologically acceptable salt is a sodium salt or potassium salt, and the pharmacologically acceptable ester is a 1-isopropoxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, pivaloyloxymethyl ester, 1-methylcyclohexylcarbonyloxymethyl ester or 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, and

(20) a compound wherein R¹ represents a 2-oxo-4-pyrrolidinyl group,

the configuration in the carbapenem skeleton is a (1R,5S,6S) configuration,

the configuration of the hydroxyl group at the a-position of the 6-substituent in the carbapenem skeleton is R a configuration,

the pharmacologically acceptable salt is a sodium salt, and

the pharmacologically acceptable ester is a 1-(isopropoxycarbonyloxy)ethyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester or pivaloyloxymethyl ester.

Specific examples of the compounds represented by the formula (I) can be exemplified in Table 1. ##STR5##

TABLE 1
Compound No.       R                  R1 a
1            H                  2-oxo-4-Pyrr
2            Na                 2-oxo-4-Pyrr
3            K                  2-oxo-4-Pyrr
4            MeOCO2 CHMe   2-oxo-4-Pyrr
5            EtOCO2 CHMe   2-oxo-4-Pyrr
6            Pri OCO2 CHMe 2-oxo-4-Pyrr
7            But OCO2 CH2  2-oxo-4-Pyrr
8            But OCO2 CHMe 2-oxo-4-Pyrr
9            Pnc OCO2 CHMe 2-oxo-4-Pyrr
10                 Hxc OCO2 CHMe 2-oxo-4-Pyrr
11                 AcOCH2        2-oxo-4-Pyrr
12                 AcOCHMe            2-oxo-4-Pyrr
13                 Pri CO2 CH2  2-oxo-4-Pyrr
14                 But CO2 CH2  2-oxo-4-Pyrr
15                 Pnc CO2 CH2  2-oxo-4-Pyrr
16                 1-MePnc CO2 CH2  2-oxo-4-Pyrr
17                 Hxc CO2 CH2  2-oxo-4-Pyrr
18                 1-MeHxCOCH2   2-oxo-4-Pyrr
19                 Phthz              2-oxo-4-Pyrr
20                 MODM               2-oxo-4-Pyrr
21                 H                  1-Me-2-oxo-4-Pyrr
22                 Na                 1-Me-2-oxo-4-Pyrr
23                 K                  1-Me-2-oxo-4-Pyrr
24                 MeOCO2 CHMe   1-Me-2-oxo-4-Pyrr
25                 EtOCO2 CHMe   1-Me-2-oxo-4-Pyrr
26                 Pri OCO2 CHMe 1-Me-2-oxo-4-Pyrr
27                 Buc OCO2 CH2  1-Me-2-oxo-4-Pyrr
28                 But OCO2 CHMe 1-Me-2-oxo-4-Pyrr
29                 Pnc OCO2 CHMe 1-Me-2-oxo-4-Pyrr
30                 Hxc OCO2 CHMe 1-Me-2-oxo-4-Pyrr
31                 AcOCH2        1-Me-2-oxo-4-Pyrr
32                 AcOCHMe            1-Me-2-oxo-4-Pyrr
33                 Pri OCO2 CH2  1-Me-2-oxo-4-Pyrr
34                 But CO2 CH2  1-Me-2-oxo-4-Pyrr
35                 Pnc CO2 CH2  1-Me-2-oxo-4-Pyrr
36                 1-MePnc CO2 CH2  1-Me-2-oxo-4-Pyrr
37                 Hxc CO2 CH2  1-Me-2-oxo-4-Pyrr
38                 1-MeHxc CO2 CH2  1-Me-2-oxo-4-Pyrr
39                 Phthz              1-Me-2-oxo-4-Pyrr
40                 MODM               1-Me-2-oxo-4-Pyrr
41                 H                  2-oxo-3-Pyrr
42                 Na                 2-oxo-3-Pyrr
43                 K                  2-oxo-3-Pyrr
44                 MeOCO2 CHMe   2-oxo-3-Pyrr
45                 EtOCO2 CHMe   2-oxo-3-Pyrr
46                 Pri OCO2 CHMe 2-oxo-3-Pyrr
47                 But CO2 CH2  2-oxo-3-Pyrr
48                 But CO2 CHMe 2-oxo-3-Pyrr
49                 AcOCH2        2-oxo-3-Pyrr
50                 AcOCHMe            2-oxo-3-Pyrr
51                 Pri CO2 CH2  2-oxo-3-Pyrr
52                 But CO2 CH2  2-oxo-3-Pyrr
53                 1-MePnc CO2 CH2  2-oxo-3-Pyrr
54                 1-MeHxc CO2 CH2  2-oxo-3-Pyrr
55                 Phthz              2-oxo-3-Pyrr
56                 MODM               2-oxo-3-Pyrr
57                 H                  1-Me-2-oxo-3-Pyrr
58                 Na                 1-Me-2-oxo-3-Pyrr
59                 K                  1-Me-2-oxo-3-Pyrr
60                 MeOCO2 CHMe   1-Me-2-oxo-3-Pyrr
61                 Pri OCO2 CHMe 1-Me-2-oxo-3-Pyrr
62                 But OCO2 CH2  1-Me-2-oxo-3-Pyrr
63                 But OCO2 CHMe 1-Me-2-oxo-3-Pyrr
64                 AcOCH2        1-Me-2-oxo-3-Pyrr
65                 AcOCHMe            1-Me-2-oxo-3-Pyrr
66                 Pri CO2 CH2  1-Me-2-oxo-3-Pyrr
67                 But CO2 CH2  1-Me-2-oxo-3-Pyrr
68                 1-MePnc CO2 CH2  1-Me-2-oxo-3-Pyrr
69                 1-MeHxc CO2 CH2  1-Me-2-oxo-3-Pyrr
70                 Phthz              1-Me-2-oxo-3-Pyrr
71                 MODM               1-Me-2-oxo-3-Pyrr
72                 H                  ImdzoPyrr
73                 Na                 ImdzoPyrr
74                 K                  ImdzoPyrr
75                 Pri OCO2 CHMe ImdzoPyrr
76                 But CO2 CH2  ImdzoPyrr
77                 Hxc CO2 CHMe ImdzoPyrr
78                 H                  ThizAze
79                 Na                 ThizAze
80                 K                  ThizAze
81                 Pri OCO2 CHMe ThizAze
82                 But CO2 CH2  ThizAze
83                 Hxc CO2 CHMe ThizAze
84                 H                  2-thioxo-4-Pyrr
85                 Na                 2-thioxo-4-Pyrr
86                 K                  2-thioxo-4-Pyrr
87                 Pri OCO2 CHMe 2-thioxo-4-Pyrr
88                 But CO2 CH2  2-thioxo-4-Pyrr
89                 Hxc CO2 CHMe 2-thioxo-4-Pyrr
90                 H                  1-Me-2-thioxo-4-Pyrr
91                 Na                 1-Me-2-thioxo-4-Pyrr
92                 K                  1-Me-2-thioxo-4-Pyrr
93                 Pri OCO2 CHMe 1-Me-2-thioxo-4-Pyrr
94                 But CO2 CH2  1-Me-2-thioxo-4-Pyrr
95                 Hxc CO2 CHMe 1-Me-2-thioxo-4-Pyrr

In the above Table, abbreviations represent the following groups, respectively.

Ac: acetyl

Bu^t : t-butyl

Et: ethyl

Hx^c : cyclohexyl

ImdzoPyrr: group of the formula (IIb)

Me: methyl

MODM: 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl

Phthz: phthalidyl

Pn^c : cyclopentyl

Pn^e : isopropyl

Pyrr: pyrrolidinyl

ThizAze: group of the formula (Ic)

In the above table, the following compounds are preferred: Compounds Nos. 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 20, 22, 23, 25, 26, 27, 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 40, 73, 76, 79, 82, 83, 85, 88, 91 and 94;

the following compounds are more preferrred: Compounds Nos. 2, 6, 10, 14, 18, 22, 26, 30, 34 and 38; and

the following compounds are much more preferred:

Compound No. 2: sodium 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3 -carboxylate,

Compound No. 14: pivaloyloxymethyl 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3 -carboxylate,

Compound No. 18: 1-methylcyclohexylcarbonyloxymethyl 2-(2-oxo4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3- carboxylate,

Compound No. 22: sodium 2-(1-methyl-2-oxo-4pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbape n-2-em-3-carboxylate, and

Compound No. 34: pivaloyloxymethyl 2-(1-methyl-2-oxo4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbape n-2-em-3-carboxylate.

On the other hand, the following compounds are most preferred:

(1R,5 S,6S)-2-[(4R-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1- carbapen-2-em-3-carboxylic acid, or the sodium salt or pivaloyloxymethyl ester thereof;

(1R,5 S,6S)-2-[(4S)-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1 -carbapen-2-em-3-carboxylic acid, or the sodium salt or pivaloyloxymethyl ester thereof;

(1R,5S,6S)-2-[(4R)-1-methyl-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethy l]-1-methyl- 1-carbapen-2-em-3-carboxylic acid, or sodium salt or pivaloyloxymethyl ester thereof; and

(1R,5S,6S)-2-[(4S)-1-methyl-2--oxo4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethy l]-1-methyl-1-carbapen-2-em-3-carboxylic acid, or sodium salt or pivaloyloxymethyl ester thereof.

Compounds (I), each of which is an active ingredient of the present invention, are known or can be prepared easily by a known method (for example Japanese Patent Application Kokai No. Hei 7-165759, Japanese Patent Application Kokai No. Hei 2-223587, Japanese Patent Application Kokai No. Hei 8-53453, Japanese Patent Application Kokai No. Hei 4-279588, etc.).

The 1-methylcarbapenem derivatives of formula (I), active ingredients of the present invention, have excellent anti-bacterial activity against various helicobacter pylori and lower toxicity, and so they are useful as an anti-bacterial agent for the treatment or prevention (particularly, treatment) of infectious diseases caused by helicobacter pylori.

When the Compound (I) is used as an anti-bacterial agent, Compound (I) by itself or a mixture with a pharmacologically acceptable excipient, diluent, etc., can be administered orally in the form of tablets, capsules, granules, powders or syrups or parenterally in the form of injections. Of these, oral administration is recommended.

The above formulations can be prepared in a known manner by using additives. Examples of the additives include an excipient (for example sugar derivatives such as lactose, sucrose, dextrose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium and internally-crosslinked carboxymethyl cellulose sodium; gum arabic; dextran; pullulan; silicate derivatives such as soft silicic acid anhydride, synthetic aluminum silicate and magnesium aluminate metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; and sulfate derivatives such as calcium sulfate), a binder (for example the above-exemplified excipients, gelatin, polyvinyl pyrrolidone and Macrogol), a disintegrator (for example the above-exemplified excipients, chemically-modified starch or cellulose derivatives such as croscarmellose sodium, carboxymethyl starch sodium and crosslinked polyvinyl pyrrolidone), a lubricant (for example talc, stearic acid, metal salts of stearic acid such as calcium stearate and magnesium stearate; colloidal silica; waxes such as veegum and spermaceti; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylates such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic acid anhydride and silicic acid hydrate; and the same starch derivatives as those exemplified for the excipient), a stabilizer (for example paraoxybenzoates such as methyl paraben and propyl paraben; alcohols such as chlorobutanol benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol derivatives such as phenol and cresol; thimerosal; acetic anhydride; and sorbic acid), a corrigent (for example, ordinarily-employed sweeteners, acidifiers and flavors), a diluent and a solution-forming agent for injections (for example, water, ethanol and glycerin). The dose of Compound (I) will vary depending upon the condition and age of the patient and the like. Orally, it is administered in an amount of 30 mg (preferably 50 mg) in a single dose as a lower limit and 5000 mg (preferably 300 mg) in a single dose as an upper limit, and intravenously, it is administered in an amount of 10 mg (preferably 30 mg) in a single dose as a lower limit and 3000 mg (preferably 200 mg) in a single dose as an upper limit. It is desirable to be administered one to six times per day depending upon the conditions of the patient, i.e., the person being treated.

The anti-helicobacter pylori agent which contains Compound (I) of the present invention as an active ingredient may contain one or more other medicaments in addition. Any medicament that does not have adverse effects on Compound (I) of the present invention can be used. Examples include bismuth preparations (such as bismuth citrate and bismuth salicylate), nitroimidazole compounds (such as metronidazole), H₂ blocker type anti-ulcereratives (such as cimetidine, ranitidine hydrochloride, famotidine, roxatidine acetate hydrochloride and nizatidine), proton-pump inhibitor type anti-ulceratives (such as omeprazole, lansoprazole, rabeprazole, reminoprazole and saviprazole), mucous membrane protective factor enhancer type anti-ulceratives (such as plaunotol, teprenone and sofalcone), anti-bacterials (such as clarithromycin, azithromycin, erythromycin, roxithromycin and amoxicillin) and synthetic anti-bacterials (such as ofloxacin, levofloxacin, ciprofloxacin); preferably the bismuth preparations, nitroimidazole compounds, H₂ blocker type anti-ulceratives, proton-pump anti-ulceratives and mucous membrane protective factor enhancer type anti-ulceratives; more preferably, cimetidine, ranitidine hydrochloride, famotidine, roxatidine acetate hydrochloride, nizatidine, omeprazole, lansoprazole, rabeprazole, reminoprazole and saviprazole; and most preferably cimetidine, ranitidine hydrochloride, famotidine, omeprazole and lansoprazole.

The present invention will hereinafter be described more specifically by tests and preparation examples. It should, however, be understood that the present invention is not limited by these examples.

(Test 1)

In vitro activity against helicobacter pylon (MIC; μg/ml)

Helicobacter pylori (H. pylori) from storage was smeared on a 7%-equine-defibrinated-blood-added brain heart infusion agar (BHIA) plate and cultured at 37°C for 72 hours under microaerophilic and wet conditions. The colonies thus grown were picked and suspended in physiological saline to prepare a culture solution of 10⁸ CFU/ml (viable microbe cell number per ml). The resulting culture solution was diluted to 10 to 50-fold with physiological saline, and one spot (about 10 μl) of the solution was inoculated on each of medicament-containing and medicament-free BHIA plates. Each of the plates was cultured at 37° C. for 72 hours under microaerophilic and wet conditions and the minimum inhibitory concentration (MIC: μg/ml) at which the growth of the colonies was inhibited was measured. The results are shown in Table 2.

TABLE 2
In vitro antibacterial activity (minimum
inhibitory concentration, MIC: μg/ml)
No. of      MIC (μg/ml)
helicobacter Compound    Compound    Compound
pylori strain No. 1       No. 2       No. 3       AMPC    CAM
9470        ≦0.006   ≦0.0006  ≦0.006   0.012   0.006
9472        ≦0.006   ≦0.006   ≦0.006   0.025   0.006
9474        ≦0.006   --     --     0.05    0.025
9824        ≦0.006   ≦0.006   ≦0.006   0.39    1.5
9828        ≦0.006   ≦0.006   ≦0.006   0.20    6.25

In the above Table 2, Compound 1 is sodium (1R,5S,6S)-2-[(4R)-2-oxo-4pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-meth yl-1-carbapen-2-em-3-carboxylate, Compound 2 is sodium (1R,5S,6S)-2-[(4R)-1-methyl-2-oxo-4-pyrrolidinylthio]-6[(1R)-1-hydroxyethy l]-1-methyl-1-carbapen-2-em-3-carboxylate, Compound 3 is sodium (1R,5S,6S)-2-[(4S)-1-methyl-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyeth yl]-1-methyl-1-carbapen-2-em-3-carboxylate, AMPC stands for amoxicillin and CAM stands for clarithromycin.

(Test 2)

Therapeutic effects for nude mouse infected with helicobacter pylon

Bacteria (helicobacter pylori 9470 strain) used for the test, which were cultured for 48 hours in a 2%-fetal-calf-serum-added brucella broth, were centrifuged. After removal of the supernatant, the residue was re-suspended in a 1/10 amount of a brucella broth. The resulting suspended solution was orally administered to each of three to five nude mice in an amount of 1.5 ml per mouse. 10 days after the infection, administration of a medicament was started. A 0.5% tragacanth suspension of a medicament was orally administered for 4 days through an oral catheter at a dose of 0.3 ml/mouse, once a day. On the day after the final administration, the stomach was extirpated, homogenized and then diluted. The viable microbe cell number (CFU/stomach) was measured and the results are shown in FIG. 1.

In FIG. 1, Medicament A is a control group, Medicaments B(1) and B(2) are CAM (clarithromycin: 1 mg/kg) and CAM (10 mg/kg), respectively, and Medicaments C(1) and C(2) are Compound 4, that is, pivaloyloxymethyl (1R,5S,6S)-2-[(4R)-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-met hyl-1-carbapen-2-em-3-carboxylate (1 mg/kg) and Compound 4 (10 mg/kg), respectively. The significant difference of Medicament B(2), Medicament C(1) or C(2) is p<0.01 (vs the control group).

(Preparation Example 1)

TBL Capsules Compound 4 50.0 mg Lactose 128.7 Corn starch 70.0 Magnesium stearate 1.3 250 mg

The above-described ingredients in powdery form were mixed, shifted through a 60-mesh sieve and used to fill a 250-mg No.3 gelatin capsule to give a capsule.

Claims

1. A method for the prophylaxis or treatment of an infectious disease caused by helicobacter pylori, which method comprises administering to a mammal suffering from or susceptible to such a disease a pharmacologically effective amount of an anti-helicobacter pylori agent, wherein said anti-helicobacter pylori agent is a 1-methylcarbapenem compound of formula (I), or a pharmacologically acceptable salt or ester thereof: ##STR6##

wherein:

R¹ represents a group of the following formula: ##STR7##

R² represents a hydrogen atom or a c₁ -c₆ alkyl group, and

R³ represents a hydrogen atom or a c₁ -c₆ alkyl group.

2. The method of treatment according to claim 1, wherein said mammal is a human.

3. The method according to claim 2, wherein R¹ is a group of formula (IIa), in which R² represents a hydrogen atom or a c₁ -c₄ alkyl group, a group of formula (IIb), a group of formula (IIc) or a group of formula (IId), in which R³ represents a hydrogen atom or a methyl group.

4. The method according to claim 2, wherein R¹ is a group of formula (IIa), in which R² represents a hydrogen atom or a methyl group.

5. The method according to claim 2 wherein R¹ is a 2-oxo-3-pyrrolidinyl, 1-methyl-2-oxo-3-pyrrolidinyl, 2-oxo4-pyrolidinyl or 1-methyl-2-oxo-4-pyrrolidinyl group.

6. The method according to claim 2, wherein R¹ is a 2-oxo-4-pyrolidinyl or 1-methyl-2-oxo-4-pyrrolidinyl group.

7. The method according to claim 2, wherein R¹ is a 2-oxo-4-pyrolidinyl group.

8. The method according to claim 2, wherein the configuration in the carbapenem skeleton is a (1R,5S,6S) configuration.

9. The method according to claim 2, wherein the configuration of the hydroxyl group at the α-position of the 6-substituent in the carbapenem skeleton is a R configuration.

10. The method according to claim 2, wherein said agent is a salt of said compound of formula (I) selected from the group consisting of lithium salts, sodium salts and potassium salts.

11. The method according to claim 2, wherein said agent is a salt of said compound of formula (I) selected from the group consisting of sodium salts and potassium salts.

12. The method according to claim 2, wherein said agent is a sodium salt of said compound of formula (I).

13. The method according to claim 2, wherein said agent is a pharmacologically acceptable ester of said compound of formula (I) which can be hydrolyzed in vivo and converted into the corresponding carboxylic acid.

14. The method according to claim 2, in which said agent is a pharmacologically acceptable ester of said compound of formula (I) selected from the group consisting of 1-(methoxycarbonyloxy)ethyl esters, 1-(ethoxycarbonyloxy)ethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters, 1-(t-butoxycarbonyloxy)ethyl esters, 1-(cyclopentyloxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters, acetoxymethyl esters, 1-(acetoxy)ethyl esters, isobutyryloxymethyl esters, 1-(isobutyryloxy)ethyl esters, pivaloyloxymethyl esters, 1-(pivaloyloxy)ethyl esters, cyclopentylcarbonyloxymethyl esters, 1-(cyclopentylcarbonyloxy)ethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, 1-(1-methylcyclopentylcarbonyloxy)ethyl esters, cyclohexylcarbonyloxymethyl esters, 1-(cyclohexylcarbonyloxy)ethyl esters, 1-methylcyclohexylcarbonyloxymethyl esters, 1-(1-methylcyclohexyl-carbonyloxy)ethyl esters, phthalidyl esters, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester and 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl esters.

15. The method according to claim 14, in which said pharmacologically acceptable ester of said compound of formula (I) is selected from the group consisting of 1-(methoxycarbonyloxy)ethyl esters, 1-(ethoxycarbonyloxy)ethyl esters, 1-(isopropoxycarbonyloxy)ethyl esters, t-butoxycarbonyloxymethyl esters, 1-(t-butoxycarbonyloxy)ethyl esters, 1-(cyclopentyloxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters, acetoxymethyl esters, 1-(acetoxy)ethyl esters, isobutyryloxymethyl esters, 1-(isobutyryloxy)ethyl esters, pivaloyloxymethyl esters, 1-(pivaloyloxy)ethyl esters, cyclopentylcarbonyloxymethyl esters, 1-methylcyclopentylcarbonyloxymethyl esters, cyclohexylcarbonyloxymethyl esters, 1-methylcyclohexylcarbonyloxymethyl esters, phthalidyl esters and 5-methyl-2-oxo-1,3-dioxolen4-ylmethyl esters.

16. The method according to claim 14, in which said pharmacologically acceptable ester of said compound of formula (I) is selected from the group consisting of 1-(isopropoxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters, pivaloyloxymethyl esters, 1-methylcyclohexylcarbonyloxymethyl esters and 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters.

17. The method according to claim 14, in which said pharmacologically acceptable ester of said compound of formula (I) is selected from the group consisting of 1-(isopropoxycarbonyloxy)ethyl esters, 1-(cyclohexyloxycarbonyloxy)ethyl esters and pivaloyloxymethyl esters.

18. The method according to claim 2, in which said agent is selected from the group consisting of:

sodium 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3 -carboxylate,

pivaloyloxymethyl 2-(2-oxo4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3- carboxylate,

1-methylcyclohexylcarbonyloxymethyl 2-(2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3 -carboxylate,

sodium 2-(1-methyl-2-oxo4-pyrrolidinylthio)-6-1-hydroxyethyl)-1-methyl-1-carbapen -2-em-3-carboxylate, and

pivaloyloxymethyl 2-(1-methyl-2-oxo-4-pyrrolidinylthio)-6-(1-hydroxyethyl)-1-methyl-1-carbap en-2-em-3-carboxylate.

19. The method according to claim 18, wherein in said agent, the configuration of the carbapenem skeleton is a (1R,5S,6S) configuration and the configuration of the hydroxyl group at the a-position of the 6-substituent in the carbapenem skeleton is a R configuration.

20. The method according to claim 2, wherein said agent is

(1R,5 S,6S)-2-[(4R-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1- carbapen-2-em-3-carboxylic acid, or the sodium salt or pivaloyloxymethyl ester thereof.

21. The method according to claim 2, wherein said agent is

(1R,5S,6S)-2-[(4S)-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-meth yl-1-carbapen-2-em-3-carboxylic acid, or the sodium salt or pivaloyloxymethyl ester thereof.

22. The method according to claim 2, wherein said agent is

(1R,5S,6S)-2-[(4R)-1-methyl-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethy l]-1-methyl-1-carbapen-2-em-3-carboxylic acid, or sodium salt or pivaloyloxymethyl ester thereof.

23. The method according to claim 2, wherein said agent is

(1R,5S,6S)-2-[(4S)-1-methyl-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethy l]-1-methyl-1-carbapen-2-em-3-carboxylic acid, or sodium salt or pivaloyloxymethyl ester thereof.

24. The method according to claim 20, wherein said agent is said sodium salt.

25. The method according to claim 20, wherein said agent is said pivaloyloxymethyl ester.

26. The method according to claim 21, wherein said agent is said sodium salt.

27. The method according to claim 21, wherein said agent is said pivaloyloxymethyl ester.

28. The method according to claim 22, wherein said agent is said sodium salt.

29. The method according to claim 22, wherein said agent is said pivaloyloxymethyl ester.

30. The method according to claim 23, wherein said agent is said sodium salt.

31. The method according to claim 23, wherein said agent is said pivaloyloxymethyl ester.

32. The method according to claim 1, wherein the method is for the treatment of an infectious disease caused by helicobacter pylori.